Hsp27 is a cell survival protein found at elevated levels in many human cancers including prostate, lung, breast, ovarian, bladder, renal, pancreatic, multiple myeloma and liver cancer. In addition, many anti-cancer therapies are known to further elevate Hsp27 levels. For example, Hsp27 levels increased four-fold in prostate cancer patients after treatment with chemo- or hormone therapy. Increased levels of Hsp27 in some human cancers are associated with metastases, poor prognosis and resistance to radiation or chemotherapy.
Hsp27 has been disclosed as a therapeutic target in the treatment of cancer. For example, U.S. Pat. No. 7,101,991 discloses antisense oligonucleotides and siRNA that inhibit Hsp27 expression. Additional oligonucleotide sequences targeting Hsp27 expression are disclosed in WO2007/025229 and US Patent Publications Nos. 2009/0264502 and 2011/0144185. Non-oligonucleotide compounds for inhibition of Hsp27 have also been disclosed, including berberine derivatives described in European Patent EP0813872, and compounds described in JP 10045572, JP 10045574, JP10036261 and JP 10036267, all assigned to Kureha Chemical Industries Co., Ltd. Paclitaxel has also been shown to be an inhibitor of Hsp27 expression. Tanaka et al., Int J Gynecol Cancer. 2004 July-August; 14(4):616-20. Nucleoside inhibitors that binds to Hsp27 are also known. One of these, bromovinyldeoxyuridine (BRDU, Brivudine, RP101) has been tested in clinical trials and shown to enhance survival of patients with pancreatic cancer. Tuukanen et al. J Cancer Res Clin Oncol. 2011 September; 137(9):1349-61.
Preclinical studies show that OGX-427, an antisense oligonucleotide described in U.S. Pat. No. 7,101,991 (Seq. ID No. 1, OncoGenex Technologies Inc.), significantly decreases levels of Hsp27, induces apoptosis in several human cancer cell lines, has single agent anti-tumor activity, and acts as a chemosensitizer in combination with several cytotoxic drugs including docetaxel. OGX-427 is being evaluated in a Phase 1 study in patients with breast, prostate, ovarian, non-small cell lung, or bladder cancer who have failed potentially curative treatments or for which a curative treatment does not exist.